US9446013B2 - Method of lowering circulating oxidized low density lipoprotein-beta-2-glycoprotein 1 complex for treatment of atherosclerosis - Google Patents

Method of lowering circulating oxidized low density lipoprotein-beta-2-glycoprotein 1 complex for treatment of atherosclerosis Download PDF

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US9446013B2
US9446013B2 US13/125,806 US200913125806A US9446013B2 US 9446013 B2 US9446013 B2 US 9446013B2 US 200913125806 A US200913125806 A US 200913125806A US 9446013 B2 US9446013 B2 US 9446013B2
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Bomi Patel Framroze
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A23L1/3006—
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • Embodiments of the invention relate to natural poly unsaturated fatty acid (PUFA) containing cooking oil compositions that lower circulating oxidized low density lipoprotein-beta-2-glycoprotein 1 complex for prevention and treatment of atherosclerosis.
  • PUFA poly unsaturated fatty acid
  • Elevated circulatory cholesterol is an established risk factor in the development of atherosclerosis.
  • Atherosclerosis can be described as the process of the weakening of arterial walls and a narrowing of the blood flow within these vessels. This sequence of events frequently occurs in the coronary arteries, causing blockage of blood flow to the heart and leading to myocardial infarction (heart damage); it is often termed coronary heart disease (CHD).
  • CHD coronary heart disease
  • Therapeutic agents such as statins, which control the concentration of serum cholesterol, have shown some effectiveness in the treatment of coronary heart disease. These agents modulate circulating levels of cholesterol-carrying, lipoproteins by inhibiting cholesterol synthesis itself, but have no effect on downstream events such as cholesterol absorption or oxidation, which are necessary steps for initiating atherosclerosis.
  • cholesterol levels are constantly under upward pressure due to high dietary intake of animal fat, and on account of the body's synthesis of cholesterol in the liver and other tissue when dietary supply is deemed inadequate.
  • lipoproteins Four major classes of lipoproteins are known, all of which share a similar basic structure of a lipid nucleus surrounded by an amphiphilic surface layer of phospholipids and apolipoproteins. The larger the lipid nucleus the less dense is the lipoprotein particle.
  • HDL high density lipoprotein
  • LDL low density lipoprotein
  • VLDL very low density lipoprotein
  • VLDL very low density lipoproteins
  • oxidized LDL oxidized LDL
  • Oxidative modification of LDL alters its biological properties, resulting in chemotaxis of monocytes or T lymphocytes in addition to the modulation of growth factors and cytokine production from endothelial cells, smooth muscle cells, and macrophages.
  • the cytotoxicity oxLDL from cultured endothelial cells has been clearly demonstrated to be atherogenic.
  • Elevated plasma oxLDL levels have been established as a biochemical risk marker for CHD.
  • the absence of association of oxLDL levels with other risk factors, such as hypertension, hyperlipidemia, or smoking suggests that raised oxLDL levels are an independent risk factor for CHD and when compared with other biochemical markers, such as total cholesterol, triglycerides, apoB, or HDL levels, the association between oxLDL, levels and CHD is a markedly superior risk indicator for CHD.
  • Adhesion molecules are inflammatory markers, which are up-regulated by oxLDL and play a pivotal role in atherogenesis.
  • Another manner in which oxLDL may be shown to contribute to CHD is by assisting in the accumulation of apoptotic cells in atherosclerotic plaques.
  • Atherosclerosis has also been characterized by a gradual thickening of arterial walls due to the excessive accumulation of lipids.
  • Pro-inflammatory factors and dyslipidemia are the main contributors to its development as described by Steinberg D., J. Biol. Chem. Vol. 272(34), pg. 20963, (1997) and Steinberg D., Nature Med. Vol. 8, pg. 1211, (2002).
  • Low density lipoprotein (LDL) is the principal form of cholesterol that accumulates in atherosclerotic lesions or plaques, but LDL must be first modified into an oxidized structure (oxLDL) to begin the process, and as shown by McMurray H. et al. J. Clinical. Med. Vol. 92, pg. 1004, (1993) the most significant pro-atherogenic mechanism for modifying LDL into oxLDL is oxidative stress.
  • oxLDL binds to ⁇ 2 GPI-glycoprotein to eventually form a stable non-dissociable complex.
  • oxLDL- ⁇ 2 GPI complex oxidized low density lipoprotein-beta-2-glycoprotein 1 complex
  • These stable complexes are regarded as pathogenic and highly clinically relevant and have been implicated as pro-atherogenic antigens and represent a serologic risk factor to the development of athero-thrombosis.
  • Myeloperoxidase is a heme peroxidase-cyclooxygenase enzyme expressed in neutrophils, monocytes and macrophages. MPO participates in the innate immune defence system by forming microbicidal reactive oxidants such as hypochlorous acid, a potent antimicrobial agent.
  • hypochlorous acid has also been reported to react with nucleobases resulting in the formation of 5-chlorouracil, a marker for DNA damage during inflammation, which is enriched in human atherosclerotic tissue.
  • MPO-derived oxidants contribute to tissue damage and the initiation and propagation of acute and chronic vascular inflammatory disease. Circulating levels of MPO have been shown to predict risks for major adverse cardiac events and specific levels of MPO-derived chlorinated compounds are known biomarkers for atherosclerosis disease progression. (Takeshita J, Byun Nhan T Q, Pritchard D K, Pennathur S, Schwartz S M et al. (2006). Myeloperoxidase generates 5-chlorouracil in human atherosclerotic tissue: a potential pathway for somatic mutagenesis by macrophages, J. Biol. Chem., 281: 3096-3104)
  • the present inventors have found that patients using a cooking oil formulation, containing fish and/or algal oil rich in mixed PUFA's, in their daily diet, over a sustained period, showed a significant reduction in circulatory oxLDL- ⁇ 2 GPI complex.
  • the positive effect of the cooking oil formulation cannot be derived from the known and described literature.
  • the present inventors followed up this unexpected result with a second trial using a once-a-day dose of fish oil capsule containing a mixture of PUFA's and showed the same surprising lowering of circulatory oxLDL- ⁇ 2 GPI complex levels as observed in the cooking oil trial.
  • the present inventors carried out a comparative trial between an oil containing predominantly a single PUFA (DHA) and an oil containing a mixture of PUFA's (DHA, EPA, DPA) and showed the surprising statistically significant additional lowering of OxLDL- ⁇ 2 GPI complex levels for the mixed PUFA's as compared to oil containing predominantly a single PUFA.
  • the present inventors discovered a surprising, statistically significant, lowering of circulatory MPO levels for patients taking an oral dose of mixed PUFA's as compared to an untreated control group.
  • Embodiments of the present invention comprise a novel method to reduce circulatory oxLDL- ⁇ 2 GPI complex and Myeloperoxidase (MPO) by providing a daily therapeutically-effective dose of at least one of Eicosa Pentaenoic Acid (EPA), Docosa Pentaenoic Acid (DPA), and Docosa Hexaenoic Acid (DHA) polyunsaturated fatty acids (PUFA) formulated into a cooking oil composition wherein at least one of EPA, DPA, and DHA is added as a constituent of fish and/or algal oil and mixed with one or more known cooking oils such as groundnut oil, rice-bran oil, soybean oil, corn oil, sesame oil, canola oil, safflower oil, live oil, peanut oil and/or other vegetable oils it to a stable cooking oil composition.
  • EPA Eicosa Pentaenoic Acid
  • DPA Docosa Pentaenoic Acid
  • DHA Docosa Hex
  • An embodiment of the present invention comprises a method to deliver a daily therapeutically-effective dose of at least one of Eicosa Pentaenoic Acid (EPA), Docosa Pentaenoic Acid (DPA), and Docosa Hexaenoic Acid (DHA) polyunsaturated fatty acids (PUFA) by providing a daily capsule of fish and or algal oil to the patient to lower circulatory OxLDL and MPO.
  • EPA Eicosa Pentaenoic Acid
  • DPA Docosa Pentaenoic Acid
  • DHA Docosa Hexaenoic Acid
  • LDL Low density lipoprotein
  • oxLDL oxidized structure
  • oxLDL binds to ⁇ 2-glycoprotein 1 to eventually form a stable non-dissociable complex (oxLDL- ⁇ 2 GPI complex).
  • the initial reaction is reversible but is followed by the formation of stable non-dissociable complexes which are regarded (Moue K. et al., Oxidized LDL/- ⁇ 2 GPI complexes. New aspects in atherosclerosis. Lupus 14, 736 (2005)) as pathogenic and highly clinically relevant.
  • the uptake of oxLDL by macrophages is mediated by a scavenger receptor CD36 which leads to the formation of foam cells with atherosclerotic plaque. (Podrez E A. et al., Macrophage scavenger receptor CD36 is the major receptor for LDL modified by monocyte-generated reactive nitrogen species. J. Clin. Invest. 105(8), 1085 (2000)).
  • oxLDL- ⁇ 2 GPI complexes have been implicated as pro-atherogenic antigens and represent a serologic risk factor and contributor to the development of athero-thrombosis.
  • Circulatory oxLDL- ⁇ 2 GPI complex can be accurately measured using an immunometric assay based on a double-antibody ‘sandwich’ technique (ELISA) that detects the circulating oxLDL- ⁇ 2 GPI complex in human plasma.
  • ELISA double-antibody ‘sandwich’ technique
  • the wells of a 96-well plate are coated with a monoclonal antibody against human ⁇ 2 GPI which will bind any ⁇ 2 GPI introduced into the well.
  • Bound oxLDL- ⁇ 2 GPI is detected using a horseradish peroxidase (HRP)-labeled monoclonal antibody directed against human apoB100.
  • HRP horseradish peroxidase
  • the concentration of oxLDL- ⁇ 2 GPI complex is determined by measuring the enzymatic activity of the HRP using the chromophore reagent tetramethylbenzidine (TMB) which forms a distinct yellow color measured at 450 nm.
  • TMB chromophore reagent tetramethylbenzidine
  • the intensity of the color produced is measured using a spectrophotometer and is directly proportional to the amount of bound oxLDL- ⁇ 2 GPI complex.
  • the results are plotted against a standard curve prepared using known solutions of the complex to arrive at the exact measure of circulatory oxLDL- ⁇ 2 GPI complex in the plasma tested.
  • a cooking oil of the present invention may be prepared by mixing standard cooking oils with 7.5% w/w algal oil, which contained a minimum of 35% EPA (20%) and DHA (80%) combined.
  • the standard cooking oils selected for the trial are commonly used Groundnut and Sunflower oils. The mixing process is carried out in a closed system under nitrogen (to prevent oxidation) and at temperatures between 20-40 degrees Celsius.
  • Patients of either sex were selected aged between 18-60 years with serum LDL cholesterol levels between 130-250 mg/DL and serum triglyceride levels between 150-500 mg/DL.
  • Each patient was subjected to a initial, intermediate (monthly), and final (three months) complete physical examination consisting of measuring RBC with platelets, electrocardiogram, 12 hour fasting lipid profile, fasting blood glucose, thyroid profile, liver function test and renal function test to be able to assess both the efficacy and side effects during the trial period.
  • Group A 3 ⁇ 500 ml of cooking oil containing 7.5% w/w of algal oil to be used for normal cooking purposes over a period of three months.
  • Group C 3 ⁇ 500 ml of standard sunflower oil to be used for normal cooking purposes over a period of three months.
  • the present inventors compared feeding 24 guinea pigs for 4 weeks a supplemental amount of predominantly a single PUFA and mixed PUFA's, to determine the effectiveness of each in lowering circulatory oxLDL-beta-2 glycoprotein complex,
  • a PUFA combination of 80% DHA, 20% EPA (AO) versus one in which the PUFA concentration is 35% DHA, 35% EPA and 30% DPA (SO) was used and the circulatory oxLDL- ⁇ 2 GPI was measured using a similar method as described in the first trial above.
  • the oxLDL- ⁇ 2 GPI complex concentration curve is first plotted sequentially diluting a reference standard solution, measuring the absorbance (at 450 nm) for each concentration and plotting the calibration curve while simultaneously measuring 24 unknown plasma samples taken in duplicate to measure the unknown concentrations of oxLDL- ⁇ 2 GPI complex in these samples as shown below in Table 1.
  • the standard solutions are shown in wells A1-F2 while the patient plasma samples are shown in wells A3-H8 run in duplicates.
  • Table 3 shows a summary of the change in circulatory oxLDL- ⁇ 2 GPI complex concentrations over the period of 3 months observed for the 54 patients from our trial.
  • the patients in test Group A who consumed the cooking oil containing the 7.5% w/w algal oil showed a statistically significant lowering in levels of circulatory oxLDL- ⁇ 2 GPI complex, which as described earlier should lead to a significant decrease in the development of athero-thrombotic diseases for these patients.
  • the mean reduction circulatory oxLDL- ⁇ 2 GPI complex in the test Group A is ⁇ 11.78% which is significantly greater than the mean reduction from control Group B at ⁇ 0.33% and the numerical increase in circulatory oxLDL- ⁇ 2 GPI complex seen from control Group C at 0.64%.
  • Statistical significance is seen with standard deviations of 0.016, 0.011 and 0.011 and a confidence level of 0.021, 0.010, 0.010 at an alpha of 0.01 for the three groups respectively.
  • the fish oil was analyzed for its lipid profile which is shown below in Table 4 and shows the presence of mixed PUFA's (EPA, DPA, DHA) and the results of the measurement of circulatory oxLDL- ⁇ 2 GPI complex is shown below in Table 5.
  • the mean reduction in circulatory oxLDL- ⁇ 2 GPI complex in the test Group F is ⁇ 9.77% which is significantly different from the numerical increase in circulatory oxLDL- ⁇ 2 GPI complex seen from control group labeled “C” at 0.54% as shown below in Table 5.
  • Statistical significance is seen with standard deviations of 0.014, 0.005 with a confidence level of 0.007 and 0.002 at an alpha of 0.05 for the F and C groups respectively.
  • Group A was fed 250 mg/kg body wt of Salmon Oil
  • Group B was fed 250 mg/kg body wt of Algal Oil
  • Each patient in group F was given a 2 ⁇ 500 mg capsule of fish oil for swallowing once a day during breakfast. Blood was drawn on the first and approximately 30 th day of treatment and circulatory MPO levels were measured in the plasma.
  • the mean reduction in circulatory MPO was measured by a modified ELISA assay at 405 nm.
  • Test Group F fish oil capsule
  • C at ⁇ 0.3% as shown below in Table 7.
  • Statistical significance is seen with standard deviations of 0.011, 0.006 with a confidence level of 0.006 and 0.003 at an alpha of 0.05 for the F and C groups respectively.
  • Embodiments of the invention are methods to reduce circulating oxLDL-beta-2-glycoprotein 1 complex and circulating MPO levels in human sera as a means of prevention and treatment of atherosclerosis comprising administering to a person an effective amount of a dietary oil composition containing 1-99 wt % polyunsaturated fatty acids (PUFA).
  • PUFA polyunsaturated fatty acids
  • Embodiments of the invention further comprise methods wherein the dietary oil composition further comprises an edible cooking oil, where the composition comprises a fatty acid distribution of saturated fatty acids (SFA) 15-55 wt %; mono unsaturated fatty acids (MUFA) 40-80 wt %; and polyunsaturated fatty acids (PUFA) 5-45 wt %.
  • SFA saturated fatty acids
  • MUFA mono unsaturated fatty acids
  • PUFA polyunsaturated fatty acids
  • Embodiments of the invention further comprise methods wherein the dietary oil composition is administered via a capsule, the capsule containing a dietary oil composition comprising a fatty acid distribution of saturated fatty acids (SFA) 5-10 wt %; mono unsaturated fatty acids (MUFA) 5-10 wt %; and polyunsaturated fatty acids (PUFA) 20-90 wt %.
  • SFA saturated fatty acids
  • MUFA mono unsaturated fatty acids
  • PUFA polyunsaturated fatty acids
  • Embodiments of the invention further comprise methods wherein the preferred polyunsaturated fatty acids are Eicosa Pentaenoic Acid (EPA), Docosa Pentaenoic Acid (DPA) and Docosa Hexaenoic Acid (DHA), preferably in a ration of 0.1-1, 0.1-0.5, and 0.5-1.
  • EPA Eicosa Pentaenoic Acid
  • DPA Docosa Pentaenoic Acid
  • DHA Docosa Hexaenoic Acid
  • Embodiments of the invention further comprise methods wherein the PUFA fraction comprises at least one oil selected from the group consisting of marine oil and algal oil, wherein the marine oil and algal oil comprise EPA, DHA, DPA and natural anti-oxidants.
  • Embodiments of the invention further comprise methods wherein the edible cooking oil comprises vegetable oil.
  • Embodiments of the invention further comprise methods wherein the edible cooking oil comprises an oil selected from the group consisting of groundnut oil, rice-bran oil, soybean oil, corn oil, sesame oil, canola oil, safflower oil, olive oil, and peanut oil.
  • the edible cooking oil comprises an oil selected from the group consisting of groundnut oil, rice-bran oil, soybean oil, corn oil, sesame oil, canola oil, safflower oil, olive oil, and peanut oil.
  • Embodiments of the invention further comprise methods wherein the edible cooking oil further comprises at least one of Vitamin A, Vitamin D, Vitamin E, or an anti-oxidant plant extract.

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